Melatonin is a hormone produced by the pineal gland in humans. This gland is about the size of a pea and is located at the centre of the brain, near its base.
It has an important role
· in the regulation of the biological clock
· as an antioxidant
· in the immune system.
Chemical Data and Pharmacology
Melatonin is 5-methoxy-N-acetyltryptamine, with the formula C13H16N2O2. It has a half-life of 35-50 minutes and is excreted in the urine after being metabolised by the liver.
Melatonin is also called acetamide, beta-methyl-6-chloromelatonin, Luzindole or N-acetyl-5-methoxytryptamine.
It is synthesized from the amino acid tryptophan by the enzyme 5-hydroxyindole-O-methyltransferase.
Melatonin is a hormone found in all living organisms, from algae to humans. Its production in humans, by the pineal gland, is under the influence of the hypothalamus (part of the brain), which receives information from the retina of the eye about the daily pattern of light and darkness. This pattern, affecting the hypothalamus and melatonin production, occurs through recently defined pathways of non-visual light detection. There are photoreceptor cells in the retina, distinct from those involved in the visual system. These cells represent approximately 2% of retinal ganglion nerve cells and express the non-visual photopigment melanopsin. This is linked to the circadian rhythm via neural and endocrine (hormonal) signals.
Expressing this more simply, the synthesis and release of melatonin are stimulated by darkness and suppressed by light and melatonin controls the circadian rhythm. (‘Circadian’ means occurring or recurring about once per day).
The melatonin produced in the pineal gland acts as an endocrine hormone since it is released into the bloodstream. By contrast, melatonin which is also produced by the retina and the gastrointestinal tract acts as a paracrine (acts locally) hormone.
Natural melatonin production decreases with age, and the decrease is associated with some sleep disorders, particularly in the elderly.
Melatonin’s Role in the Biological Clock
The melatonin signal forms part of the system that regulates the circadian cycle by chemically causing drowsiness to fall upon the mind, but it is the central nervous system that controls the daily cycle in most components of both the paracrine and endocrine systems, rather than just the melatonin signal, as was once postulated.
The production of melatonin, ‘the hormone of darkness’, by the pineal gland is inhibited by light and permitted by darkness. Its secretion peaks in the middle of the night and gradually decreases during the second half of the night.
Artificial lighting reduces the longer hours of darkness in winter in temperate climates, to eight hours or less per day all the year around. Even low light levels inhibit melatonin production to some extent and over-illumination can create significant reduction.
It is believed that the production of melatonin is reduced each time sleep is interrupted and a bright light is turned on. This suggests that a lower level of night light would be safer. Others have suggested that short exposures to light at night do no harm.
Melatonin, as a medicinal supplement, appears to have some benefit against circadian rhythm sleep disorders such as jet-lag. It can hasten sleep. It can do so without the hazards or side effects of prescription sleeping pills.
Melatonin as an Antioxidant
Although the primary site of melatonin’s action in humans is the melatonin receptors, it first evolved as an antioxidant. In many lower forms of life, it serves only this purpose.
Melatonin is a powerful antioxidant. It easily crosses the cell membranes and the blood-brain barrier.
Unlike other antioxidants, melatonin does not undergo redox cycling, ie the ability of a molecule to undergo reduction and oxidation repeatedly. Other antioxidants, such as vitamin C, undergo redox cycling. Melatonin, once oxidized, cannot revert it its former state because it forms several stable end-products upon reacting with free radicals. Melatonin’s capacity to absorb free radicals extends at least to its quaternary metabolites, a process referred to as ‘the free radical scavenging cascade’. This is not true with other conventional antioxidants.
In animal models, melatonin has been demonstrated to prevent damage to DNA by some carcinogens, stopping the mechanism by which they cause cancer. Reduced melatonin production has been proposed as a likely factor in the significantly higher cancer rates in night workers, and the effect of modern lighting practice on endogenous melatonin has been proposed as a contributory factor to the high incidence of some cancers in the developed world.
The antioxidant activity of melatonin may play a role in preventing certain cardiac conditions, especially arrhythmias, and may increase longevity; it has been shown to increase the life-span of mice by 20% in some studies.
Melatonin and the Immune System
While it is clear that melatonin interacts with the immune system, the details of these interactions are unclear.
A search using the keywords “melatonin and immune” reveals hundreds of papers and reviews describing various immunological effects of melatonin.
Current research is exploring the role of melatonin as an immuno-modulator in cancer.
Melatonin as a Medicinal Supplement
Melatonin has been studied for the treatment of a number of disorders.
The website of MedlinePlus (a service of the U.S. National Library of Medicine and the National Institute of Health), lists 36 “uses based on scientific evidence” for melatonin. These uses have been tested in humans or in animals. Each of the listed conditions is described and the benefits from melatonin set out.
MedlinePlus grade the 36 uses as follows:
Grade A - strong scientific evidence for this use
Grade B - good scientific evidence for this use
Grade C - unclear scientific evidence for this use
· Grade A (1)
· Grade B (4)
Delayed sleep phase syndrome
Insomnia in the elderly
Sleep disturbance in children with neuro-psychiatric disorders
Sleep enhancement in healthy people
· Grade C (31). These are listed alphabetically and include:
Alzheimer’s disease (sleep disorders)
Antioxidant (free-radical scavenging)
Attention deficit hyperactivity disorder (ADHD)
Bipolar disorder (sleep disturbances)
Depression (sleep disturbances)
High blood pressure (hypertension)
Inflammatory bowel disease (IBS)
Insomnia (of unknown origin in the non-elderly)
Schizophrenia (sleep disorders)
Seasonal Affective Disorder (SAD)
Ultraviolet light skin damage protection
Workshift sleep disorder
Full details can be found in the MedlinePlus website nlm.nih.gov/medlineplus. (Click on ‘Drugs & Supplements’, then from the second offering ‘Herbs and Supplements’ select M, then select melatonin).
MedlinePlus also lists 55 uses based on tradition or scientific theories, including ageing, cancer prevention, cognitive and memory enhancement, fibro-myalgia, multiple sclerosis, prevention of sudden infant death syndrome (SIDS) and withdrawal from narcotics.
Sources of Supplemental Melatonin
‘Natural’, ‘animal’ or’ bovine grade’ melatonin contains the actual extracts of the pineal gland. Because the extract comes from animal tissue, this grade of melatonin may be accompanied by viruses or proteins that could cause an antibody response leading to allergy. It is recommended that this form is not used.
The alternative is synthetic or pharmacy grade melatonin, which is produced from pharmaceutical ingredients. This form is molecularly identical to the melatonin produced by the human body.
Dosage of Supplemental Melatonin
There is no established dosage for melatonin that is widely accepted.
The Mayo Clinic sets out a dosage regime for the various conditions listed above. For example, they suggest
· 3-5mg for insomnia in the elderly
· 0.5-5.0mg for jet-lag.
· 1-5mg for insomnia of unknown origin (in the non-elderly)
All dosages are taken as a single dose at night-time, at a recommended 30-60 minutes before bedtime. For jet-lag, the time to target is the bedtime at the destination.
Dosages are designed to raise melatonin levels for several hours to enhance the quality of sleep. It should be noted that some studies suggest smaller doses are just as effective at improving sleep quality. High dose melatonin can even be counter-productive. In one study, 0.5mg of melatonin was effective, while 20mg was not.
There has been limited study of melatonin supplements in children. For children, the starting dose should be 0.25mg.
Safety of Supplemental Melatonin
Melatonin is practically non-toxic and exhibits almost no short-term side effects. It is generally regarded as safe. The U.S. National Institute of Health states: “Available trials report that overall adverse effects are not significantly more common with melatonin than placebo”.
In one extensive clinical trial, 75mg of melatonin per day was given to 1400 women in the Netherlands for up to four years with no ill effects.
There is generally no morning-after hangover effect as is common with sleeping tablets. Expect to wake up normally, well refreshed and full of energy.
Many people who take melatonin as a supplement report an increase in the frequency and vividness of dreams. High doses (50mg) dramatically increase REM sleep time (during the dream phase of sleep there are rapid eye movements, ‘REM’) and dream activity.
There is the occasional report of symptoms resulting from even small doses of melatonin, generally in chemically sensitive individuals. These include extreme drowsiness, with overactive mind and incoordination, headache and depression. If this happens, a very small dose (0.25mg or less) should be tried and, if tolerated, gradually increased.
Because melatonin causes somnolence, it should not be taken within five hours (or caution exercised) before driving, operating machinery etc. Since melatonin is taken just before bedtime, this is generally not an issue.
Melatonin should be avoided in patients using Warfarin and possibly in patients taking other blood-thinning medications or with clotting disorders. It my also interact with heart or blood pressure medications, making close monitoring necessary.
Melatonin is a necessary hormone, essential for healthful sleep and for its other benefits such as its antioxidant and immunological effects.
Good sleep, in a dark room, without exposure to light during the night, will ensure maximum natural production.
Where indicated for a condition, oral supplements are well worthwhile considering, as part of the overall therapeutic approach to the particular condition.
Another useful website is melatonin.com.
* Copyright 2008: The Huntly Centre.
Disclaimer: All material on the huntlycentre.com.au website is provided for informational or educational purposes only. Consult a health professional regarding the applicability of any opinions or recommendations expressed herein, with respect to your symptoms or medical condition.
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